The Functional Effect of Rare Variants in Complement Genes on C3b Degradation in Patients With Age-Related Macular Degeneration
The Functional Effect of Rare Variants in Complement Genes on C3b Degradation in Patients With Age-Related Macular Degeneration
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DOI：
10.1001/jamaophthalmol.2016.4604
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发表时间：
2017-01-01
影响因子：
8.1
通讯作者：
den Hollander, Anneke I.
中科院分区：
文献类型：
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作者：
Geerlings, Maartje J.;Kremlitzka, Mariann;den Hollander, Anneke I.
重要性在年龄相关性黄斑变性（AMD）中，补体系统中的罕见变异体已经被描述，但是它们的功能后果在很大程度上仍未被探索。目的鉴定补体基因中新的罕见变异体，并确定所鉴定的变异体对来自携带者和非携带者的血清样品中的补体水平和补体调节的功能作用。本研究评估了22个AMD家族的受累（n = 114）和未受累（n = 60）成员，以及一个病例对照队列，该队列由来自2006年3月29日欧洲遗传数据库的1831名无关AMD患者和1367名对照个体组成，到2013年4月26日，在荷兰的奈梅亨和德国的科隆。针对补体因子H（CFH）、补体因子I（CFI）、补体C9（C9）和补体C3（C3）基因中的罕见变体过滤家族的外显子组测序数据。病例对照组用等位基因特异性分析进行基因分型。血清样品从已鉴定的变体的携带者（n = 177）和年龄匹配的非携带者（n = 157）获得。主要结果和指标CFH、CFI、C9和C3基因罕见变异与AMD的相关性，相应蛋白的血清水平，结果1831例无血缘关系的AMD患者的平均年龄为75.0（9.4）岁，女性占60.5%。1367名无关对照参与者的平均（SD）年龄为70.4（7.0），58.7%为女性。所有人都是欧洲人后裔。CFH、CFI、C9和C3的罕见变异导致AMD发生风险增加（比值比，2.04; 95%CI，1.47-2.82; P
IMPORTANCE In age-related macular degeneration (AMD), rare variants in the complement system have been described, but their functional consequences remain largely unexplored.OBJECTIVES To identify new rare variants in complement genes and determine the functional effect of identified variants on complement levels and complement regulation in serum samples from carriers and noncarriers.DESIGN, SETTING, AND PARTICIPANTS This study evaluated affected (n = 114) and unaffected (n = 60) members of 22 families with AMD and a case-control cohort consisting of 1831 unrelated patients with AMD and 1367 control individuals from the European Genetic Database from March 29, 2006, to April 26, 2013, in Nijmegen, the Netherlands, and Cologne, Germany. Exome sequencing data of families were filtered for rare variants in the complement factor H (CFH), complement factor I (CFI), complement C9 (C9), and complement C3 (C3) genes. The case-control cohort was genotyped with allele-specific assays. Serum samples were obtained from carriers of identified variants (n = 177) and age-matched noncarriers (n = 157). Serum concentrations of factor H (FH), factor I (FI), C9, and C3 were measured, and C3b degradation ability was determined.MAIN OUTCOMES AND MEASURES Association of rare variants in the CFH, CFI, C9, and C3 genes with AMD, serum levels of corresponding proteins, and C3b degradation ability of CFH and CFI variant carriers.RESULTS The 1831 unrelated patients with AMD had a mean (SD) age of 75.0 (9.4) years, and 60.5% were female. The 1367 unrelated control participants had a mean (SD) age of 70.4 (7.0), and 58.7% were female. All individuals were of European descent. Rare variants in CFH, CFI, C9, and C3 contributed to an increased risk of developing AMD (odds ratio, 2.04; 95% CI, 1.47-2.82; P